Article Metrics


Online attention

Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering

DOI: 10.1074/jbc.M110.182394 DOI Help
PMID: 21156796 PMID Help

Authors: Chao Yu (The University of Oxford) , Andreas F.-P. Sonnen (The University of Oxford) , Roger George (University College London) , Benoit H. Dessailly (University College London) , Loren J. Stagg (University of Texas M.D. Anderson Cancer Center) , Edward J. Evans (The University of Oxford) , Christine A. Orengo (University College London) , David I. Stuart (The University of Oxford) , John E. Ladbury (University College London; University of Texas M.D. Anderson Cancer Center) , Shinji Ikemizu (Kumamoto University) , Robert J. C. Gilbert (The University of Oxford) , Simon J. Davis (The University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 286 , PAGES 6685-6696.

State: Published (Approved)
Published: December 2011

Open Access Open Access

Abstract: The inhibitory T-cell surface-expressed receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which belongs to the class of cell surface proteins phosphorylated by extrinsic tyrosine kinases that also includes antigen receptors, binds the related ligands, B7-1 and B7-2, expressed on antigen-presenting cells. Conformational changes are commonly invoked to explain ligand-induced "triggering" of this class of receptors. Crystal structures of ligand-bound CTLA-4 have been reported, but not the apo form, precluding analysis of the structural changes accompanying ligand binding. The 1.8-Å resolution structure of an apo human CTLA-4 homodimer emphasizes the shared evolutionary history of the CTLA-4/CD28 subgroup of the immunoglobulin superfamily and the antigen receptors. The ligand-bound and unbound forms of both CTLA-4 and B7-1 are remarkably similar, in marked contrast to B7-2, whose binding to CTLA-4 has elements of induced fit. Isothermal titration calorimetry reveals that ligand binding by CTLA-4 is enthalpically driven and accompanied by unfavorable entropic changes. The similarity of the thermodynamic parameters determined for the interactions of CTLA-4 with B7-1 and B7-2 suggests that the binding is not highly specific, but the conformational changes observed for B7-2 binding suggest some level of selectivity. The new structure establishes that rigid-body ligand interactions are capable of triggering CTLA-4 phosphorylation by extrinsic kinase(s).

Journal Keywords: Antigens; CD; Antigens; CD80; Antigens; CD86; Binding; CHO; CTLA-4; Cricetinae; Cricetulus; Crystallography; X-Ray; Humans; Protein; Tertiary; Receptors; Antigen; T-Cell; Thermodynamics

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 04/04/2012 12:08


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)